Multimorbidity and the associated use of multiple medicines (polypharmacy), is common in the older population. Despite this, there is no consensus definition for polypharmacy. A systematic review was conducted to identify and summarise polypharmacy definitions in existing literature. The reporting of this systematic review conforms to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist. MEDLINE (Ovid), EMBASE and Cochrane were systematically searched, as well as grey literature, to identify articles which defined the term polypharmacy (without any limits on the types of definitions) and were in English, published between 1st January 2000 and 30th May 2016. Definitions were categorised as i. numerical only (using the number of medications to define polypharmacy), ii. numerical with an associated duration of therapy or healthcare setting (such as during hospital stay) or iii. Descriptive (using a brief description to define polypharmacy). A total of 1156 articles were identified and 110 articles met the inclusion criteria. Articles not only defined polypharmacy but associated terms such as minor and major polypharmacy. As a result, a total of 138 definitions of polypharmacy and associated terms were obtained. There were 111 numerical only definitions (80.4% of all definitions), 15 numerical definitions which incorporated a duration of therapy or healthcare setting (10.9%) and 12 descriptive definitions (8.7%). The most commonly reported definition of polypharmacy was the numerical definition of five or more medications daily (n = 51, 46.4% of articles), with definitions ranging from two or more to 11 or more medicines. Only 6.4% of articles classified the distinction between appropriate and inappropriate polypharmacy, using descriptive definitions to make this distinction. Polypharmacy definitions were variable. Numerical definitions of polypharmacy did not account for specific comorbidities present and make it difficult to assess safety and appropriateness of therapy in the clinical setting.

The two cyclooxygenase (COX) isoforms, COX-1 and COX-2, both metabolize arachidonic acid to PGH2, the common substrate for thromboxane A2 (TXA2), prostacyclin (PGI2), and PGE2 synthesis. We characterized the synthesis of these prostanoids in HUVECs in relation to COX-1 and COX-2 activity. Untreated HUVEC expressed only COX-1, whereas addition of IL-1β caused induction of COX-2. TXA2 was the predominant COX-1-derived product, and TXA2 synthesis changed little with up-regulation of COX-2 by IL-1β (2-fold increase). By contrast, COX-2 up-regulation was associated with large increases in the synthesis of PGI2 and PGE2 (54- and 84-fold increases, respectively). Addition of the selective COX-2 inhibitor, NS-398, almost completely abolished PGI2 and PGE2 synthesis, but had little effect on TXA2 synthesis. The up-regulation of COX-2 by IL-1β was accompanied by specific up-regulation of PGI synthase and PGE synthase, but not TX synthase. An examination of the substrate concentration dependencies showed that the pathway of TXA2 synthesis was saturated at a 20-fold lower arachidonic acid concentration than that for PGI2 and PGE2 synthesis. In conclusion, endothelial prostanoid synthesis appears to be differentially regulated by the induction of COX-2. The apparent PGI2 and PGE2 linkage with COX-2 activity may be explained by a temporal increase in total COX activity, together with selective up-regulation of PGI synthase and PGE synthase, and different kinetic characteristics of the terminal synthases. These findings have particular importance with regard to the potential for cardiovascular consequences of COX-2 inhibition.

The prevalence of comorbidity is high, with 80% of the elderly population having three or more chronic conditions. Comorbidity is associated with a decline in many health outcomes and increases in mortality and use of health care resources. The aim of this study was to identify, review and summarise studies reporting the prevalence of comorbidity of chronic diseases in Australia.

Objectives To determine the impact of comorbid chronic diseases on mortality in older people. Design Prospective cohort study (1992–2006). Associations between numbers of chronic diseases or mutually exclusive comorbid chronic diseases on mortality over 14 years, by Cox proportional hazards model adjusting for sociodemographic variables or Kaplan–Meier analyses, respectively. Setting Population based, Australia. Participants 2087 randomly selected participants aged ≥65 years old, living in the community or institutions. Main results Participants with 3–4 or ≥5 diseases had a 25% (95% CI 1.05 to 1.5, p=0.01) and 80% (95% CI 1.5 to 2.2, p<0.0001) increased risk of mortality, respectively, by comparison with no chronic disease, after adjusting for age, sex and residential status. When cardiovascular disease (CVD), mental health problem or diabetes were comorbid with arthritis, there was a trend towards increased survival (range 8.2–9.5 years) by comparison with CVD, mental health problem or diabetes alone (survival 5.8–6.9 years). This increase in survival with arthritis as a comorbidity was negated when CVD and mental health problems or CVD and diabetes were present in disease combinations together. Conclusion Older people with ≥3 chronic diseases have increased risk of mortality, but discordant effects on survival depend on specific disease combinations. These results raise the hypothesis that patients who have an increased likelihood of opportunity for care from their physician are more likely to have comorbid diseases detected and managed.

There is an autocrine relationship between eicosanoid and cytokine synthesis, with the ratio of prostaglandin E₂ (PGE₂)/thromboxane A₂ (TXA₂) being one of the determinants of the level of cytokine synthesis. In monocytes, cyclooxygenase type 1 (COX-1) activity appears to favor TXA₂ production and COX-2 activity appears to favor PGE₂ production. This has led to speculation regarding possible linkage of COX isozymes with PGE and TXA synthase. We have studied the kinetics of PGE₂ and TXA₂ synthesis under conditions that rely on COX-1 or -2 activity. With small amounts of endogenously generated prostaglandin H₂ (PGH₂), TXA₂ synthesis was greater than PGE₂. With greater amounts of endogenously generated PGH₂, PGE₂ synthesis was greater than TXA₂. Also, TXA synthase was saturated at lower substrate concentrations than PGE synthase. This pattern was observed irrespective of whether PGH₂ was produced by COX-1 or COX-2 or whether it was added directly. Furthermore, the inhibition of eicosanoid production by the action of nonsteroidal anti-inflammatory drugs or by the prevention of COX-2 induction with the p38 mitogen-activated protein kinase inhibitor SKF86002 was greater for PGE₂ than for TXA₂. It is proposed that different kinetics of PGE synthase and TXA synthase account for the patterns of production of these eicosanoids in monocytes under a variety of experimental conditions. These properties provide an alternative explanation to notional linkage or compartmentalization of COX-1 or -2 with the respective terminal synthases and that therapeutically induced changes in eicosanoid ratios toward predominance of TXA₂ may have unwanted effects in long-term anti-inflammatory and anti-arthritic therapy.